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A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury
Sophie Casey1,2,3, Kate Goasdoue4, Stephanie M Miller4
1Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland. Sophie.casey@umail.ucc.ie.
Insights
Early detection of hypoxic ischemic encephalopathy (HIE) in infants is crucial. This study identifies specific microRNAs (miRNAs) in cord blood as rapid biomarkers for timely HIE diagnosis and intervention.
Area of Science:
- Neonatal neurology
- Biomarker discovery
- Molecular biology
Background:
- Hypoxic ischemic encephalopathy (HIE) is a leading cause of infant brain injury, necessitating early diagnostic markers.
- Previous research identified microRNAs (miRNAs) in cord blood of HIE infants, but their precise timing remained unclear.
Purpose of the Study:
- To investigate the serial changes and functional relevance of circulating miRNAs in a porcine model of neonatal HIE.
- To identify early, clinically relevant biomarkers for HIE diagnosis and therapeutic intervention.
Main Methods:
- Utilized a porcine model to induce neonatal HIE and collected serial blood samples.
- Quantified six specific miRNAs (miR-374a, miR-181b, miR-181a, miR-151a, miR-148a, miR-128) post-hypoxia-ischemia (HI).
- Correlated miRNA levels with histopathological injury and MRS Lac/Cr ratios; performed bioinformatic analysis and in vitro functional assays.
Main Results:
- Six miRNAs were rapidly upregulated within 1 hour post-HI, with miR-374a, miR-181b, and miR-181a specific to moderate-severe HIE.
- Histopathological injury and five miRNAs correlated positively and predicted MRS Lac/Cr ratios.
- Inhibition of miR-181a promoted neurite outgrowth and increased BMPR2 expression in neuronal cells.
Conclusions:
- Specific circulating miRNAs serve as rapid, early biomarkers for neonatal HIE.
- These miRNAs may play a role in regulating neuronal survival pathways, such as the BMP signaling pathway.
- Early miRNA detection facilitates timely diagnosis and therapeutic strategies for HIE.
Abstract:
Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs-miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128-were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival.
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